Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma
Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma
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DOI：
10.1093/carcin/23.6.1017
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发表时间：
2002-06-01
期刊：
影响因子：
4.7
通讯作者：
Bueno, R
中科院分区：
文献类型：
--
作者：
Gordon, GJ;Appasani, K;Bueno, R
恶性胸膜间皮瘤（MPM）是一种高度致命的胸膜肿瘤，通常对包括顺铂在内的化疗药物具有耐药性，并且对其致癌途径知之甚少。我们使用差异显示来比较间皮瘤、正常胸膜和正常肺中的基因表达模式，以便更好地了解 MPM 病理学，并寻找可能促进这种癌症耐药性的基因。人类凋亡抑制剂蛋白1基因（IAP-1/MIHC/cIAP2）被发现在MPM中高表达。我们通过多种方法（包括实时定量逆转录 PCR 和蛋白质印迹分析）证实了 IAP-1 mRNA 和蛋白质在另外 39 个人类 MPM 肿瘤标本和 3/5 (60%) MPM 细胞系中的过度表达。使用反义靶向方法，我们发现 IAP-1 mRNA 水平的减弱会降低基线细胞活力，并使 MPM 细胞系对顺铂的敏感性增加近 20 倍。 IAP-1 基因表达减少还会导致 caspase 9 促凋亡裂解产物的一致增加和存活肿瘤细胞数量的减少。我们的观察强烈表明，IAP-1 至少部分负责促进许多 MPM 肿瘤的癌发生和介导对顺铂的耐药性，并且有必要进一步研究这种凋亡途径。
Malignant pleural mesothelioma (MPM) is a highly lethal pleural neoplasm that is often resistant to chemotherapeutic drugs, including cisplatin, and for which little is known regarding carcinogenic pathways. We used differential display to compare gene expression patterns in mesothelioma, normal pleura and normal lung, in order to better understand MPM pathobiology, and to search for genes that may facilitate drug resistance in this cancer. The human inhibitor of apoptosis protein-1 gene (IAP-1/MIHC/cIAP2) was discovered to be highly expressed in MPM. We confirmed overexpression of IAP-1 mRNA and protein in 39 additional human MPM tumor specimens and 3/5 (60%) MPM cell lines by multiple methods, including real time quantitative reverse transcription-PCR and western blot analysis. Using an antisense targeting approach, we found that attenuation of IAP-1 mRNA levels decreases baseline cell viability and increases the sensitivity of MPM cell lines to cisplatin by nearly 20-fold. Reduced IAP-1 gene expression also results in a concordant increase of the pro-apoptotic cleavage product of caspase 9 and a reduction in the number of viable tumor cells. Our observations strongly suggest that IAP-1 is at least partly responsible for promoting carcinogenesis and mediating resistance to cisplatin in many MPM tumors and that further study of this apoptotic pathway is warranted.